The phosphotidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway encompasses a number of signaling points which are critical in the control of cell growth and survival. P70 S6 kinase is a serine-threonine protein kinase which is a downstream effector of the PI3K/AKT/mTOR signaling pathway. P70 S6 kinase phosphorylates the ribosomal protein S6 in cells and regulates ribosome biogenesis, cell growth and cell cycle progression in response to mitogenic stimulation. P70 S6 kinase is commonly activated in many solid tumors. Inhibitors of p70 S6 kinase, which are useful in the treatment of such tumors, are disclosed in WO 2006/046024 and WO 2008/075109.
Epidermal growth factor receptor (EGFR) is a trans-membrane glycoprotein which belongs to a family of structurally related receptor tyrosine kinases. EGFR feeds into the PI3K/AKT/mTOR pathway at the cell surface level. EGFR is believed to be important in multiple signal-transduction pathways and appears to play a critical role in both tumorigenesis and tumor growth. EGFR and its ligands are overexpressed or involved in autocrine growth loops in a number of tumor types. EP 0 817 775 discloses a series of 4-(substitutedphenylamino)quinazoline derivatives which have EGFR inhibitory activity and are useful in the treatment of cancer.
There exists a need for improved therapies for the treatment of cancers. Furthermore, there is a need for therapies having greater efficacy than existing therapies. Preferred combination therapies of the present invention show greater efficacy than treatment with either therapeutic agent alone. More preferred combination therapies of the present invention show greater efficacy when sub-optimal doses of each of the therapeutic agents are administered.